Compositions and methods for systemic nucleic acid sequence delivery

Abstract

The present invention provides systemic nucleic acid sequence delivery without conventional systemic administration aids (SAAs). In certain embodiments, vascular permeability agents (VPAs), such as VEGF, are used in conjunction with nucleic acid viral vectors, such as adeno-associated virus (AAV). The present invention also provides methods of treating disease by co-administration of nucleic cid sequences encoding Igf-1 and dystrophin or dystrophin-like proteins.

1. A method of systemic transduction of skeletal muscle tissue or heart tissue comprising;
 a) providing;
 i) a first composition comprising adeno-associated vectors, wherein said adeno-associated vectors comprise a nucleic acid sequence of interest, 
 ii) a second composition comprising a systemic transduction enhancing agent, wherein said systemic transduction enhancing agent comprises empty adeno-associated viral capsids, and wherein at least 50% of the adeno-associated viral capsids in said second composition are said empty adeno-associated viral capsids, and 
 iii) a subject comprising a first type of extravascular tissue, wherein said first type of extravascular tissue is skeletal muscle tissue or heart tissue; and 
 
 b) administering said first and second compositions systemically to said subject, under conditions such that said first type of extravascular tissue is transduced by said adeno-associated vectors, wherein said first and second compositions are: i) administered simultaneously; ii) are administered within 5 minutes of each other, or iii) mixed together prior to said administering. 
 
     
     
       2. The method of  claim 1 , wherein at least approximately 95% of the adeno-associated viral capsids in said second composition are said empty adeno-associated viral capsids. 
     
     
       3. The method of  claim 1 , wherein said first and second compositions are administered simultaneously or within 5 minutes of each other. 
     
     
       4. The method of  claim 1 , wherein said first and second compositions are mixed together prior to said administering. 
     
     
       5. The method of  claim 1 , wherein said first or second composition further comprises heparin. 
     
     
       6. The method of  claim 1 , wherein said first type of extravascular tissue is heart tissue. 
     
     
       7. The method of  claim 1 , wherein said first type of extravascular tissue is skeletal muscle tissue. 
     
     
       8. The method of  claim 1 , wherein said adeno-associated vectors comprise an AAV6 capsid. 
     
     
       9. The method of  claim 1 , wherein said first composition is a vasodilating agent-free composition. 
     
     
       10. The method of  claim 1 , wherein said second composition is a vasodilating agent-free composition. 
     
     
       11. The method of  claim 1 , wherein said first composition comprises less than 1×10 12  adeno-associated vectors per milliliter. 
     
     
       12. The method of  claim 1 , wherein said nucleic acid sequence of interest encodes a micro-dystrophin, micro-utrophin, micro-dystrophinlutrophin hybrid, or insulin-like growth factor 1 (Igf-1). 
     
     
       13. The method of  claim 1 , wherein said nucleic acid sequence of interest is a reporter gene. 
     
     
       14. The method of  claim 1 , wherein said administering is without a systemic administration aid.